Enterohemorrhagic Escherichia coli (EHEC) O157:H7 strains are major human food-borne pathogens, responsible for bloody diarrhea and hemolytic uremic syndrome (HUS) worldwide. So far, there is no vaccine for humans against EHEC infections.
Enterohemorrhagic Escherichia coli (EHEC) strains are zoonotic extracellular pathogens, members of the Shiga-toxin producing E. coli (STEC) pathogroup. EHEC causes sporadic outbreaks of diarrhea and hemorrhagic colitis, particularly in developed countries [reviewed in (1-3)]. In the United States, EHEC causes approximately 0.9 cases per 100,000 inhabitants, with a significant number of hospitalizations and death, particularly among children and the elderly [reviewed in (4, 5)]. E. coli 0157:H7 comprises the serotype most commonly associated with outbreaks (6) and the expression of Shiga toxin (Stx), in addition to be linked to hemorrhagic colitis, it is associated with the progression to the hemolytic uremic syndrome (HUS), which cause renal failure and high fatality rate [reviewed in (7)]. In addition, EHEC 0157:H7 uses a type 3 secretion system (T3SS) to translocate effector proteins into the eukaryotic cell, causing changes in the host cytoskeleton, ultimately leading to improved bacterial adherence and colonization and, in some cases, host cell death (8). The EHEC T3SS is comprised of a basal A TP-dependent secretion apparatus, with an EscC polymer ring spanning bacterial outer membrane and a needle like structure formed by polymers of the EscF protein and an extension structure comprised of polymerized EspA. Finally, the EspD and EspB proteins form a translocon structure in the host membrane (9-11).
Generally asymptomatic, ruminants are the principal EHEC reservoir. Contaminated meat or fresh produce resulting from animal shedding constitutes an important route for human infection (12). Current prevention efforts are centered in the elimination of animal colonization, whether by vaccination or by improving sanitary and breeding practices (12, 13). Once the human infection is acquired, supportive care is provided, since antibiotic treatment could induce Shiga toxin expression. To date, two vaccines able to reduce EHEC colonization in cattle are commercially available (13, 14). Nevertheless, development of other subunit-based vaccines has been focused in the T3SS and its associated proteins, as well as Stx (4, 12). For example, inactivated Stx-derivatives are able to induce Stx-neutralizing antibodies in mice (15, 16) and hybrid A-B subunit-derived Stx toxins also induce antibody production and increase survival against toxemia and EHEC challenge in vivo (17-19). Fusion proteins comprising of Stx-derived peptides and T3SS-related proteins are promising vaccine candidates. St2B-Tir-Stx1 B-Zot, Stx2B-Stx1 B-lnt281, EspA-Stx2A 1, EspA-IntiminC300-Stx2B and Stx2B-BLS fusions have been demonstrated to reduce EHEC colonization in animal models, such as mice and goats (20-27). Overall, cumulative information indicates that mucosal delivery routes seem to be an effective way to induce immune responses to block the adhesion of EHEC in the intestine, mainly through expression of secretory lgA (slgA) (4).
In addition to the worldwide outbreaks caused by STEC 0157:H7, this organism has come recently under renewed scientific investigation as a result of the emergence of a subpopulation of strains that have acquired critical virulence factors that contribute to more severe and lethal disease in humans (28, 29). Further, the discovery of cattle reservoirs shedding high levels of STEC 0157:H7, which has been associated with the transmission between animals and across the human-animal interface (30, 31), strongly supports the idea that adoption of vaccination for livestock and/or susceptible individuals will have significant public health benefits, preventing substantial numbers of human STEC 0157 cases (32). Therefore, further discovery for EHEC-specific antigens needs to be done to improve existing or to develop novel vaccines.